Somatostatin (SRIF), a tetradecapeptide discovered by Brazeau et al., has been shown to have potent inhibitory effects on various secretory processes in tissues such as pituitary, pancreas and gastrointestinal tract. SRIF also acts as a neuromodulator in the central nervous system. These biological effects of SRIF, all inhibitory in nature, are elicited through a series of G protein coupled receptors, of which five different subtypes have been characterized and are referred to as somatostatin type-1 receptor to somatostatin type-5 receptor (SSTR-1 to SSTR-5). These five subtypes have similar affinities for the endogenous SRIF ligands but have differing distribution in various tissues. SRIF binds to the five distinct receptor (SSTR) subtypes with relatively high and equal affinity for each subtype. SRIF produces a variety of effects, including modulation of hormone release, e.g., growth hormone, glucagon, insulin, amylin, and neurotransmitter release. Some of these effects have been associated with its binding to a specific SRIF receptor. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (“SSTR-2”) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 268:G102 (1995)), while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (“SSTR-5”) (Coy, et al. 197:366-371 (1993)). Activation of types 2 and 5 have been associated with growth hormone (GH) suppression and more particularly GH secreting adenomas (acromegaly) and thyroid-stimulating hormone (TSH) secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas.
As is well known to those skilled in the art, SRIF and analogs thereof are useful in the treatment of a great variety of diseases and/or conditions. An exemplary but by no means exhaustive list of such diseases and/or conditions would include: Cushing's Syndrome (see Clark, R. V. et al, Clin. Res. 38, p. 943A, 1990); gonadotropinoma (see Ambrosi B., et al., Acta Endocr. (Copenh.) 122, 569-576, 1990); hyperparathyroidism (see Miller, D., et al., Canad. Med. Ass. J., Vol. 145, pp. 227-228, 1991); Paget's disease (see, Palmieri, G. M. A., et al., J. of Bone and Mineral Research, 7, (Suppl. 1), p. S240 (Abs. 591), 1992); VIPoma (see Koberstein, B., et al., Z. Gastroenterology, 28, 295-301, 1990 and Christensen, C., Acta Chir. Scand. 155, 541-543, 1989); nesidioblastosis and hyperinsulinism (see Laron, Z., Israel J. Med. Sci., 26 No. 1, 1-2, 1990, Wilson, D. C., Irish J. Med. Sci., 158, No. 1, 31-32, 1989 and Micic, D., et al., Digestion, 16, Suppl. 1.70. Abs. 193, 1990); gastrinoma (see Bauer, F. E., et al., Europ. J. Pharmacol., 183, 55 1990); Zollinger-Ellison Syndrome (see Mozell, E., et al., Surg. Gynec. Obstet., 170, 476-484, 1990); hypersecretory diarrhea related to acquired immunodeficiency syndrome (AIDS) and other conditions (due to AIDS, see Cello, J. P., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A163 1990; due to elevated gastrin-releasing peptide, see Alhindawi, R., et al., Can. J. Surg., 33, 139-142, 1990; secondary to intestinal graft vs. host disease, see Bianco J. A., et al., Transplantation, 49, 1194-1195, 1990; diarrhea associated with chemotherapy, see Petrelli, N., et al., Proc. Amer. Soc. Clin. Oncol., Vol. 10, P 138, Abstr. No. 417 1991); irritable bowel syndrome (see O'Donnell, L. J. D., et al., Aliment. Pharmacol. Therap., Vol. 4., 177-181, 1990); pancreatitis (see Tulassay, Z., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A238, 1990); Crohn's Disease (see Fedorak, R. N., et al., Can. J. Gastroenterology, 3, No. 2, 53-57, 1989); systemic sclerosis (see Soudah, H., et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A129, 1990); thyroid cancer (see Modigliani, E., et al., Ann., Endocr. (Paris), 50, 483-488, 1989); psoriasis (see Camisa, C., et al., Cleveland Clinic J. Med., 57, No. 1, 71-76, 1990); hypotension (see Hoeldtke, R. D., et al., Arch. Phys. Med. Rehabil., 69, 895-898, 1988 and Kooner, J. S., et al., Brit. J. Clin. Pharmacol., 28 735P-736P, 1989); panic attacks (see Abelson, J. L., et al., Clin. Psychopharmacol., 10, 128-132, 1990); scleroderma (see Soudah, H., et al., Clin. Res., Vol. 39, p. 303A, 1991); small bowel obstruction (see Nott, D. M., et al., Brit. J. Surg., Vol. 77, p. A691, 1990); gastroesophageal reflux (see Branch, M. S., et al., Gastroenterology, Vol. 100, No. 5, Part 2 Suppl., p. A425, 1991); duodenogastric reflux (see Hasler, W., et al., Gastroenterology, Vol. 100, No. 5, Part 2, Suppl., p. A448, 1991); Graves' Disease (see Chang, T. C., et al., Brit. Med. J., 304, p. 158, 1992); polycystic ovary disease (see Prelevic, G. M., et al., Metabolism Clinical and Experimental, 41, Suppl. 2, pp 76-79, 1992); upper gastrointestinal bleeding (see Jenkins, S. A., et al., Gut., 33, pp. 404-407, 1992 and Arrigoni, A., et al., American Journal of Gastroenterology, 87, p. 1311, (abs. 275), 1992); pancreatic pseudocysts and ascites (see Hartley, J. E., et al., J. Roy. Soc. Med., 85, pp. 107-108, 1992); leukemia (see Santini, et al., 78, (Suppl. 1), p. 429A (Abs. 1708), 1991); meningioma (see Koper, J. W., et al., J. Clin. Endocr. Metab., 74, pp. 543-547, 1992); and cancer cachexia (see Bartlett, D. L., et al., Surg. Forum., 42, pp. 14-16, 1991).
Other indications associated with activation of the SRIF receptor subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; retinopathy; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
It is preferred to have an analog which is selective for the specific SRIF receptor subtype or subtypes responsible for the desired biological response, thus, reducing interaction with other receptor subtypes which could lead to undesirable side effects. Further, because of the short half-life of native SRIF, various SRIF analogs have been developed, e.g., for the treatment of acromegaly. (Raynor, et al., Molecular Pharmacol. 43:838 (1993)) The development of potent, smaller SRIF agonists led to the discovery of differing affinities of the various truncated ligands for the different subtypes. It appears that Trp8-Lys9 residue often is present in ligands that are recognized by the receptor. The Trp8-Lys9 residue forms part of a β-bend which is usually stabilized via substitution of D- for L-Trp, cyclization of the backbone, a disulfide bridge, or all constraints. One unintended consequence of such structural simplification, carried out before the discovery of multiple receptor subtypes, was the loss of broad spectrum binding affinity. This is typified by the high type 2 but low type 1, 3, 4, and 5 affinities of peptides in the OCTREOTIDE® series. Thus, the many basic biological studies with this type of analogue failed to detect effects mediated by all but one of the SRIF receptor subtypes.
We have discovered that peptide backbone constraint can be introduced by N-alkylation. This modification largely restricts the affected residue and the amino acid preceding it to an extended conformation and additionally blocks potential intramolecular hydrogen bonding sites and also proteolytic enzyme cleavage sites thus potentially enhancing pharmacokinetic properties of a peptide. Only a few N-methyl amino acids are commercially available and their synthesis is tedious. However, in another aspect of the present invention, we have discovered a procedure to N-methylate truncated SRIF analogues at every amino acid residue using the solid-phase procedure, adopted from that reported by Miller and Scanlan, (J. Am. Chem. Soc. 1997, 119, 2301-2302).
In one aspect the invention relates to a peptide according to formula (I):A1-cyclo[Cys-A2-D-Trp-A3-A4-Cys]-A5-Y1,  (I)wherein:A1 is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C3-6)alkylalanine;A2 is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C3-6)alkylalanine;A3 is Lys or Orn;A4 is β-Hydroxyvaline, Ser, hSer, or Thr;A5 is β-Hydroxyvaline, Ser, hSer, or Thr; andY1 is OH, NH2 or NHR1, where R1 is (C1-6)alkyl;wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C3-6)alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO2, OH, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, Bzl, O-Bzl, and NR9R10, where R9 and R10 each is independently H or (C1-6) alkyl; andwherein the amine nitrogen of one or more peptide bond is substituted with a methyl group; and further provided that said compound is not D-Phe-cyclo[Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys]-Thr-NH2;or a pharmaceutically acceptable salt thereof.
A preferred group of compounds of formula (I) are those compounds wherein:
A1 is Phe, D-Phe, Tyr, D-Tyr, β-Nal, D-β-Nal, Cha or D-Cha;
A2 is Phe, Tyr, β-Nal or Cha; and
Y1 is OH or NH2;
or a pharmaceutically acceptable salt thereof.
A preferred group of compounds of the immediately foregoing group of compounds are those compounds wherein A1 is D-Phe or Tyr; or wherein A2 is Phe; or wherein A3 is Lys; or wherein A4 is Thr; or wherein A5 is Thr; or a pharmaceutically acceptable salt thereof.
In a still more preferred embodiment the invention features a compound of formula (I) wherein said compound is according to the formula:
D-Phe-{(N-Me-Cys)-Phe-D-Trp-Lys-Thr-Cys}-Thr-NH2;
D-Phe-cyclo{Cys-(N-Me-Phe)-D-Trp-Lys-Thr-Cys}-Thr-NH2;
D-Phe-{Cys-Phe-(N-Me-D-Trp)-Lys-Thr-Cys}-Thr-NH2;
D-Phe-{Cys-Phe-D-Trp-(N-Me-Lys)-Thr-Cys}-Thr-NH2;
D-Phe-cyclo{Cys-Phe-D-Trp-Lys-Thr-(N-Me-Cys)}-Thr-NH2;
D-Phe-cyclo{Cys-Phe-D-Trp-Lys-Thr-Cys}-(N-Me-Thr)-NH2;
Tyr-{(N-Me-Cys)-Phe-D-Trp-Lys-Thr-Cys}-Thr-NH2;
Tyr-{Cys-(N-Me-Phe)-D-Trp-Lys-Thr-Cys}-Thr-NH2;
Tyr-{Cys-Phe-(N-Me-D-Trp)-Lys-Thr-Cys}-Thr-NH2;
Tyr-{Cys-Phe-D-Trp-(N-Me-Lys)-Thr-Cys}-Thr-NH2;
Tyr-{Cys-Phe-D-Trp-Lys-(N-Me-)Thr-Cys}-Thr-NH2;
Tyr-{Cys-Phe-D-Trp-Lys-Thr-(N-Me-Cys)}-Thr-NH2; or
Tyr-{Cys-Phe-D-Trp-Lys-Thr-Cys}-(N-Me-Thr)-NH2;
or a pharmaceutically acceptable salt thereof.
In another aspect, the invention features a compound according to formula (II),
wherein
A1 is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A2 is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, β-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A3 is β-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A6 is Val, Ala, Leu, Ile, Nle, Thr, Abu, or Ser;
A7 is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, β-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, CL, Br, F, OH, OCH3 or NO2;
A8 is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, Phe, β-Nal, β-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
each R1 and R2, independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; wherein the amine nitrogen of one or more amide peptide bond is substituted with a methyl group;
provided that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and that A1, A2, A7 and A8 cannot all be aromatic amino acids;
or a pharmaceutically acceptable salt thereof.
In one embodiment the invention features a compound according to formula (II) wherein said compound is selected from the list consisting of:
H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
H-D-Phe-p-NO2-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2;
H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;
H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; and
H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH2;
wherein the amine nitrogen of one or more peptide bond is substituted with a methyl group;
or a pharmaceutically acceptable salt thereof.
In another embodiment the invention features a peptide selected from the list of peptides, denoted “group III”, consisting of:
D-β-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH2;
D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;
Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH;
Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH;
Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH;
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH2 (an amide bridge formed between Lys* and Asp);
Ac-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-L-hArg(Et)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt;
Ac-L-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt;
Ac-hArg(CH3; hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-hArg(hexyl2)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Propionyl-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys(iPr)-Thr-Cys-Thr-NH2;
Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg(Et)2-NH2;
Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Ac-D-hArg(Et)2-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH2;
H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2;
cyclo[Pro-Phe-D-Trp-Lys(Me)-Thr-Phe];
cyclo[Pro-Phe-D-Trp-Lys(Me)-Thr-Phe];
cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe);
cyclo[Ala(Me)-Tyr-D-Trp-Lys-Thr-Phe];
cyclo[Pro-Tyr-D-Trp-Lys-Thr-Phe];
cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe];
cyclo[Pro-Phe-L-Trp-Lys-Thr-Phe];
cyclo[Pro-Phe-D-Trp(F)-Lys-Thr-Phe];
cyclo[Pro-Phe-Trp(F)-Lys-Thr-Phe];
cyclo[Pro-Phe-D-Trp-Lys-Ser-Phe];
cyclo[Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe];
cyclo[D-Ala-D-Phe(Me)-D-Thr-D-Lys-Trp-D-Phe];
cyclo[D-Ala-D-Phe(Me)-D-Val-Lys-D-Trp-D-Phe];
cyclo[D-Ala-D-Phe(Me)-D-Thr-Lys-D-Trp-D-Phe];
cyclo[-Abu-D-Phe(Me)-D-Val-Lys-D-Trp-D-Tyr];
cyclo[Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe];
cyclo[Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe];
cyclo[Ala(Me)-Tyr-D-Trp-Lys-Val-Phe];
cyclo[Ala(Me)-Tyr-D-Trp-t-4-AchxAla-Thr-Phe];
cyclo[Pro-Tyr-D-Trp-4-Amphe-Thr-Phe];
cyclo[Pro-Phe-D-Trp-4-Amphe-Thr-Phe];
cyclo[Ala(Me)-Tyr-D-Trp-4-Amphe-Thr-Phe];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba];
cyclo[Asn-Phe-D-Trp-Lys-Thr-Phe];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH2)4CO];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu]-OH;
cyclo[Phe-Phe-D-Trp-Lys-Thr-Phe];
cyclo[Phe-Phe-D-Trp-Lys-Thr-Phe-Gly];
cyclo[Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly];
cyclo[Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba];
cyclo[Asn-Phe-Phe-D-Trp(NO2)-Lys-Thr-Phe-Gaba];
cyclo[Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba];
cyclo[Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(tBu)-Gaba];
cyclo[Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys]-OH;
cyclo[Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys]-OH;
cyclo[Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys]-OH;
cyclo[Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys]-OH;
cyclo[Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba];
cyclo[Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba];
cyclo[Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Phe-Gaba];
cyclo[Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH—(CH2)3—CO];
cyclo[Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba];
cyclo[Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba];
cyclo[Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba];
H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2;
or a pharmaceutically acceptable salt thereof, wherein a disulfide bond exists in those compounds having two Cys residues and where the amine nitrogen of one or more peptide bond is substituted with a methyl group.
In a further aspect the present invention features SRIF agonists comprising the N-methylated analogs of the SRIF agonists covered by formulae or those specifically recited in the publications set forth below.
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The compounds of formula (I), formula (II) and group (III) of the instant application are useful for the same uses as SRIF, dependent upon the binding specificity or lack thereof, as may be determined by the binding assays described herein.
Thus in another aspect the invention is featured a method of binding one or more of human somatostatin subtype receptors-1, -2, -3, -4 and -5, which comprises the step of administering one or more compounds of formula (I) and/or formula (II) and/or group (III), or a pharmaceutically acceptable salt(s) of such compound or compounds, to a recipient in need thereof.
In a preferred embodiment of the immediately foregoing method is featured a method of eliciting a somatostatin agonist effect, which comprises the step of administering one or more compounds of formula (I) and/or formula (II) and/or group (III), or a pharmaceutically acceptable salt(s) of such compound or compounds, to a recipient in need thereof.
In a more preferred embodiment of the immediately foregoing method is featured a method of treating a disease or condition in a human or other animal in need thereof, which comprises administering one or more compounds of formula (I) and/or formula (II) and/or group (III), or a pharmaceutically acceptable salt(s) of such compound or compounds, to said human or other animal, wherein said disease or condition is selected from the group consisting of Cushings Syndrome, gonadotropinoma, hyperparathyroidism, Paget's disease, VIPoma, nesidioblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory diarrhea related to AIDS and other conditions, irritable bowel syndrome, pancreatitis, Crohn's Disease, systemic sclerosis, thyroid cancer, psoriasis, hypotension, panic attacks, sclerodoma, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Graves' Disease, polycystic ovary disease, upper gastrointestinal bleeding, pancreatic pseudocysts, pancreatic ascites, leukemia, meningioma, cancer cachexia, acromegaly, restenosis, hepatoma, lung cancer, melanoma, inhibiting the accelerated growth of a solid tumor, decreasing body weight, treating insulin resistance, Syndrome X, prolonging the survival of pancreatic cells, fibrosis, hyperlipidemia, hyperamylinemia, hyperprolactinemia and prolactinomas.
With the exception of the N-terminal amino acid, all abbreviations (e.g., Phe for A1) of amino acids in this disclosure stand for the structure of —NH—CH(R)—CO—, wherein R in the immediately foregoing formula is the side chain of an amino acid (e.g., CH3 for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of (R1R2)—N—CH(R)—CO—, wherein R is a side chain of an amino acid and R1 and R2 are as defined herein.
The nomenclature for the somatostatin receptor subtypes is in accordance with the recommendations of IUPHAR, in which SSTR-4 refers to the receptor originally cloned by Bruno et al., and SSTR-5 refers to the receptor cloned by O'Carroll et al. Abbreviations of the common amino acids are in accordance with the recommendations of IUPAC-IUB. The following are abbreviations of certain α-amino acids as may appear herein:
Abu =α-ammobutyric acidAib =α-aminoisobutyric acid;Ala =alanine;β-Ala =β-(3-pyridyl)-alanine;Ala(Me) =N-methyl alanine;AchxAla =aminocyclohexylalanine;Amp =4-amino-phenylalanine;Arg =arginine;hArg(Bu) =N-guanidino-(butyl)-homoarginine;hArg(CH2CF3)2 =N,N′=guanidine-bis-(2,2,2,-trifluoroethyl)-homo-arginine;hArg(CH3;hexyl) =N,N′-guanidino-(methyl, hexyl)-homoarginine;hArg(Et)2 =N,N′-guanidino-(dimethyl)-homoarginine;hArg(hexyl2) =N,N′-guanidino-(dihexyl)-homoarginine;Asp =aspartic acid;Ava =5-aminovaleric acid;Bmp =β-mercaptopropionyl;Cha =cyclohexylalanine;Cys =cysteine;Gaba =γaminobutyric acid;Glu =glutamic acid;Gln =glutamine;Gly =glycine;His =histidine;Ile =isoleucine;Leu =leucine;Leu(Me) =N-methyl leucine;Lys =lysine;Lys(Ac) =N-ε-acetyl-L-lysine;Lys(iPr) =N-isopropyllysine;Lys(Me) =N-methyllysine;Met =methionine;β-Nal =β-(2-naphthyl)alanine;Nle =norleucine;Nva =norvaline;Orn =ornithine;Pal =β-(3-pyridinyl)alanine;Pen =pencillamine;Phe =phenylalanine;4-Cl—Phe =(4-chlorophenyl)alanine;Q-chloro-Phe =(p-chlorophenyl)alanine;Phe(I) =4-iodo-phenyl)alanine;Phe(Me) =N-methyl phenylalanine;Q-NO2—Phe =(p-nitrophenyl)alanine;2,4-dichloro-Phe =β-(2,4-dichlorophenyl)alanine;pentafluoro-Phe =β-(2,3,4,5,6-pentaflurophenyl)alanine;AmPhe =aminomethylphenylalanine;Pro =proline;Ser =serine;hSer =homoserine;Thr =threonine;Tpo =4-thioproline;Trp =tryptophan;Trp(Br) =5-bromo-tryptophan;Trp(F) =5-fluoro-tryptophan;Trp(NO2) =5-nitro-tryptophan;Tyr =tyrosine;Tyr(tBu) =t-butyl-tyrosine; andVal =valine.Additional abbreviations include:
DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene;
DCM, dichloromethane;
DIC, dicyclohexylcarbodiimide;
DIEA, diisopropyethylamine;
DMF, dimethylformamide;
MTBD, 1,3,4,6,7,8-Hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine;
NPS, 2-nitrophenylsulfonyl;
TBTU, O-Benzotri-azol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; and
TFA, trifluoroacetic acid.
The amine nitrogen of peptide bond which has been substituted with a methyl group for a particular compound is indicated in the formula as follows: (N-Me-amino acid). An amino acid which has been substituted with a methyl group, in contrast, is indicated as follows: amino acid(Me). For example, in the claimed compound Tyr-{Cys-Phe-D-Trp-(N-Me-Lys)-Thr-Cys}-Thr-NH2, the amine nitrogen of the peptide bond between D-tryptophan in the 4th position and lysine in the 5th has been substituted with a methyl group whereas in the claimed compound Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH2, a hydrogen of the amino group found in the side chain of the lysine residue in the 6th position has been substituted with a methyl group.
A compound of the present invention or pharmaceutically acceptable salt thereof can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 25 μg/kg/day to 100 mg/kg/day of body weight daily are administered as a single dose or divided into multiple doses to humans and other animals, e.g., mammals, to obtain the desired therapeutic effect.
A preferred general dosage range is 250 μg/kg/day to 5.0 mg/kg/day of body weight daily which can be administered as a single dose or divided into multiple doses.
Further, a compound of the present invention or pharmaceutically acceptable salt thereof can be administered in a sustained release composition such as those described in the following patents. Among those formulations, 14-day or 28-day slow release formulations will be preferred. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a peptide and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a peptide in a gelable form. U.S. Pat. No. 5,821,221 teaches polymeric sustained release compositions comprising a peptide and chitosan. U.S. Pat. No. 5,916,883 teaches sustained release compositions comprising a peptide and cyclodextrin. International Patent Application No. PCT/US99/01180, (publication no. WO 99/38536, Aug. 5, 1999), teaches absorbable sustained release compositions of a peptide. The contents of the foregoing patents and applications are incorporated herein by reference.
The use of immediate or of sustained release compositions depends on the type of indications targeted. If the indication consists of an acute or over-acute disorder, a treatment with an immediate form will be preferred over the same with a prolonged release composition. On the contrary, for preventive or long-term treatments, a prolonged release composition will generally be preferred.